Transforming growth factor-beta (TGF-.beta.) is a member of a family of structurally related cytokines that elicit a variety of responses, including growth, differentiation, and morphogenesis, in many different cell types. (Roberts, A. B. and H. B. Sporn, In: Peptide Growth Factors and Their Receptors, Springer-Verlag, Heidelberg, pp. 421-472 (1990); Massague, J., Annu. Rev. Cell. Biol. 6: 597-641 (1990)) In vertebrates at least five different forms of TGF-.beta., termed TGF-.beta.1 to TGF-.beta.5, have been identified; they all share a high degree (60%-80%) of amino-acid sequence identity. While TGF-.beta.1 was initially characterized by its ability to induce anchorage-independent growth of normal rat kidney cells, its effects on most cell types are anti-mitogenic. (Altschul, S. F. et al., J. Mol. Biol. 215: 403-410 (1990); Andres, J. L. et al., J. Cell. Biol. 109: 3137-3145 (1989)) It is strongly growth-inhibitory for many types of cells, including both normal and transformed epithelial, endothelial, fibroblast, neuronal, lymphoid, and hematopoietic cells. In addition, TGF-.beta. plays a central role in regulating the formation of extracellular matrix and cell-matrix adhesion processes.
In spite of its widespread effects on cell phenotype and physiology, little is known about the biochemical mechanisms that enable TGF-.beta. family members to elicit these varied responses. Three distinct high-affinity cell-surface TGF-.beta.-binding proteins, termed type I, II and III, have been identified by incubating cells with radiolabelled TGF-.beta.1, cross-linking bound TGF-.beta.1 to cell surface molecules, and analyzing the labelled complexes by polyacrylamide gel electrophoresis. (Massague, J. and B. Like, J. Biol. Chem. 260: 2636-2645 (1985); Cheifetz, S. et al. J. Biol. Chem. 261: 9972-9978 (1986).) The binding constants are about 5-50 pM for the type I and II receptor and 30-300 pM for the type III receptor. (Boyd, F. T. and J. Massague, J. Biol. Chem. 264: 2272-2278 (1989))
The type I and II receptors, of estimated 53 and 70-100 kilodaltons mass respectively, are N-glycosylated transmembrane proteins that are similar in many respects. Each of these receptors has a distinct affinity for each member of the TGF-.beta. family of ligands. (Boyd, F. T. and J. Massague, J. Biol. Chem. 264: 2272-2278 (1989)) In contrast, the type III receptor shows comparable affinities for all TGF-.beta. isotypes; the type III receptor is the most abundant cell-surface receptor for TGF-.beta. in many cell lines (upwards of 200,000 per cell), and is an integral membrane proteoglycan. It is heavily modified by glycosaminoglycan (GAG) groups, and migrates heterogeneously upon gel electrophoresis as proteins of 280 to 330 kilodaltons. When deglycosylated with heparitinase and chondrontinase, the protein core migrates as a 100-110 kilodalton protein. The TGF-.beta. binding site resides in this protein core, as non glycosylated forms of this receptor that are produced in cell mutants defective in GAG synthesis are capable of ligand binding with affinities comparable to those of the natural receptor. (Cheifetz, S. and J. Massague, J. Biol. Chem., 264: 12025-12028 (1989) A variant form of type III receptor is secreted by some types of cells as a soluble molecule that apparently lacks a membrane anchor. This soluble species is found in low amounts in serum and in extracellular matrix.
The type III receptor, also called betaglycan, has a biological function distinct from that of the type I and II receptors. Some mutant mink lung epithelial cell (Mv1Lu) selected for loss of TGF-.beta. responsiveness no longer express type I receptors; others, similarly selected, lose expression of both the type I and II receptors. However, all these variants continue to express the type III receptor. (Boyd, F. T. and J. Hassague, J. Biol. Chem. 264: 2272-2278 (1989); Laiho, M. et al., J. Biol. Chem. 265: 18518-18524 (1990)) This has led to the proposal that types I and II receptors are signal-transducing molecules while the type III receptor, may subserve some other function, such as in concentrating ligand before presentation to the bona fide signal-transducing receptors. The secreted form of type III receptor, on the other hand, may act as a reservoir or clearance system for bioactive TGF-.beta..
Additional information about-each of these TGF-.beta. receptor types would enhance our understanding of their roles and make it possible, if desired, to alter their functions.